Multiple myeloma remains essentially an incurable disease despite modern chemotherapy ana Done marrow stem cell transplantation. Immunotherapy is an attractive approach in multiple myeloma since it is more specific, less toxic and possesses memory that could provide long-term immunosurveillance to reduce disease relapse following stem cell transplantation. However, there is at present a general lack of suitable- candidate antigens for this purpose. The idiotypic protein (Id) produced by myeloma cells is clone specific and has been used for immunotherapy. Unfortunately Id is a very weak antigen. Although Id-specific immune responses have been successfully induced in patients by vaccination of Id, the immune responses were generally weak and the associated antitumor responses sub-optimal. We hypothesize that, in addition to Id, myeloma cells express other novel and unique antigens that may be suitable for immune targeting. Identification of these antigens forms the basis for future design of potent polyvalent tumor vaccines for multiple myeloma. We have recently applied the serological screening of expression cDNA library (SEREX) technology to multiple myeloma and have isolated 24 clones reactive with high titer IgG in the autologous serum. In this proposal, we will characterize these clones molecularly and immunologically. We will obtain the full-length sequences of these 24 clones, carry out -sequence homology search and mutational studies, determine the prevalence of expression of the transcripts and antibodies in myeloma patients and generate recombinant proteins for novel sequences to study the ability of these gene products to elicit potentially beneficial antitumor immune responses. Successful completion of this project will form the basis for the rational design of polyvalent vaccines for multiple myeloma.